This invention relates to providing novel pharmaceutical compositions for local delivery and sustained release of non-steroidal, anti-inflammatory drugs (NSAIDS) from biocompatible, biodegradable poly(DL-lactide-co-glycolide) (PLGA) microspheres. The resulting product is applied locally into soft tissues surrounding a surgical incision or traumatic wound site where it will locally sustain release of the NSAID.
The invention also relates to providing novel pharmaceutical compositions for local delivery and sustained release of lidocaine PLGA microspheres.
Non-steroidal anti-inflammatory drugs (NSAIDS) have been effective in reducing inflammation and inducing analgesia; however, the conventional oral dosage forms of these drugs characteristically have short half-lives and irritate the gastrointestinal mucosa. Further, currently available slow release oral dosage forms, such as Biovail (enteric coated, double-layer tablets which release the drug for 12-24 hours) still result in inefficient systemic delivery of the drug and potential gastrointestinal irritation.
Therefore, currently available slow release oral dosage forms of NSAIDs induces systemic effects and the drug is not efficiently used at the site of inflammation.
Further, in the currently available slow release oral dosage forms of NSAIDs, fillers or additives are needed in order to accelerate or retard drug release.
Further still, large doses of NSAIDs administered by conventional dosing regimens often times result in toxicity and secondary pathology such as gastrointestinal tissue irritation.
Several publications and patents are available for sustained release of active agents from biodegradable polymers, particularly, poly(lactide/glycolides) (PLGA). Prior usages of PLGA for controlled release of polypeptides have involved the use of molar ratios of lactide/glycolide (L/G) of 75/25 to 100/0 for molecular weights  greater than 20,000. Further, prior art preparations of PLGA utilized fillers or additives in the inner aqueous layer to improve stability and encapsulation efficiency and/or to increase the viscosity of the aqueous layer, thereby modulating polymer hydrolysis and the biologically active agent or polypeptide release.
In addition, the prior art use of PLGA copolymers were end-capped, in that the terminal carboxyl end groups were blocked. In these end-capped co-polymers, the microcapsule preparations exhibited a low to moderate burst release of xcx9c10-14% of the entrapped polypeptide in the first 24 hours after placement in an aqueous physiological environment. In part, these characteristics are due to the use of fillers in the inner aqueous phase. Further, a 1-month release of polypeptide is known with the use of a 75/25 co-polymer of PLGA of Mw  less than 20,000.
Investigations in controlled release research has been proceeding especially to obtain a 1-2 month delivery system for biologically active agents or polypeptides using poly(lactide/glycolide) polymers. However, most of these systems have one or more of the following problems: poor encapsulation efficiency and large xe2x80x98burst releasexe2x80x99 followed by an intermediate xe2x80x98no releasexe2x80x99 or xe2x80x98lag phasexe2x80x99 until the polymer degrades. In general, release from these polymers occur over a period from about 4 weeks to about several months. In addition, in order to achieve this release a 50/50 co-polymer of Mw greater than 30,000 or a 75/25 co-polymer of Mw greater than 10,000 are employed which often results in residual polymer remaining at the site of administration long after the release of active core.
This invention provides novel pharmaceutical compositions for local delivery and sustained release of non-steroidal, anti-inflammatory drugs (NSAIDs) from biocompatible, biodegradable poly(DL-lactide-co-glycolide) (PLGA) microspheres. The resulting product is applied locally into soft tissues surrounding a surgical incision or traumatic wound site where it will locally sustain release the NSAID. In the context of this invention, ketoprofen, is preferred. Ketoprofen is an important non-steroidal anti-inflammatory drug, and is formulated into a drug delivery system that releases the drug in an aqueous solution or soft tissue for 7-60 days, depending upon its formulation.
The invention also provides novel pharmaceutical compositions for local delivery and sustained release of lidocaine PLGA microspheres.
One object of the invention is to provide biodegradable PLGA microspheres for sustained delivery of NSAIDs.
Another object of the invention is to provide sustained, local delivery of NSAIDs, for durations greater than 24 hours and for up to 2 months from a single dose.
A further object of the invention is to provide NSAID-loaded microspheres suitable for use as or incorporation with pulp capping materials in dental restoratives.
A still further object of the invention is to provide NSAID-loaded microspheres suitable for incorporation in bioadhesives or gel formulations to be used in wound or trauma sites and as an oral bandage for painful mouth lesions.
A yet further object of the invention is to provide oral dosage forms incorporating compositions of NSAID-loaded micropheres of this invention to deliver the microspheres to the gastrointestinal lumen where they can be adsorbed within the epithelium and sustain release their contents systemically.
A further object yet still of the invention is to provide the benefits of local pain obtusion and thereby allow for decreased dosing of the systemic medications such as broad action opioids.
A further object yet still is to provide sustained released lidocaine PLGA microspheres for the treatment of dental pain.
In general the excipients used in the PLGA formulation have molar compositions ranging from 100/0 to 50/50 lactide/glycolide with molecular weights of 10-100 kDa. In addition, two forms of the PLGA can be employed; namely: 1) the more hydrophobic end-capped polymer with the terminal residues functionalized as esters; and 2) the more hydrophillic uncapped polymer with the terminal residues existing as carboxylic acids.
The NSAID-loaded microspheres are prepared by two distinct processes, solvent evaporation and solvent extraction.
In the solvent evaporation process, the NSAID and PLGA were dissolved in a volatile organic solvent, preferably methylene chloride, and dispersed in an aqueous phase containing an emulsion stabilizer. Evaporation of the organic phase gave NSAID-loaded microspheres. Depending on processing parameters, the microspheres released the NSAID for a duration of 2 weeks to 2 months with minimal burst release.
In the solvent extraction process for preparing the NSAID-loaded microspheres, the NSAID and PLGA were dissolved in a polar organic solvent, preferably acetonitrile, which was dispersed in a non-polar organic phase, preferably mineral oil. The emulsion produced was then poured into a hydrocarbon solvent, preferably heptane. As the polar organic phase was extracted into the hydrocarbon, the microspheres formed. The microspheres produced released NSAID for 7 to 10 days displaying near zero-order kinetics.
In the case when the NSAID is ketoprofen, in both the solvent evaporation process and the solvent extraction process, the microspheres obtained contained 1-20% ketoprofen (w/w).